Age-related cognitive decline has been documented across many species including rodents, non-human primates, and humans. Normal cognitive aging, while accompanied by structural preservation of the brain, represents a significant compromise of the dynamic mechanisms of learning-related plasticity. One of these dynamic mechanisms that may be altered is epigenetic modification. Recent work has elucidated a link between epigenetic alterations and learning and memory. I would like to examine the role of epigenetic modifications in cognitive aging using lesion-induced and age-associated models of cognitive impairment. Utilizing a fornix-lesion model in conjunction with an established rodent model of cognitive aging will inform the specificity of age-associated molecular changes as well as the importance of subcortical inputs in normal cognitive aging. The proposed studies seek to break new ground toward defining the cell biological mechanisms of age-related cognitive decline as well as explore a novel target for therapeutic intervention on a rat model of neurocognitive aging. Histone acetylation, histone acetyltransferase (HAT) levels, histone deacetylase (HDAC) nucleocytoplasmic shuttling, and histone deacetylase inhibitor treatment will be examined in relation to learning dependency, effect of fornix lesion, and effect of age-associated cognitive decline. These studies seek to determine the role of epigenetics in normal age-associated cognitive decline and examine the therapeutic potential of HDAC inhibitors. The proposed studies have great relevance to public health. The results of this proposal will further our understanding of the molecular underpinnings of the normal cognitive decline associated with aging. Most importantly, the proposed studies directly examine the therapeutic potential of a class of molecules already currently used for the treatment of a variety of pathologies ranging from cancer to epilepsy. In fact, a clinical pilot study examining the effect of vorinostat, an HDAC inhibitor, on cognitive ability in myelodysplastic syndrome patients at the sponsoring institution is currently in the early stages of development